The aims of the present research are to study low density lipoprotein (LDL) receptors of cancer cells in a well-defined model of pancreatic acinar cell carcinoma and to gain further insight into the mechanism(s) underlying aberrant behavior of neoplastic cells. As a part of our broader investigation on the pathogenesis of acinar cell carcinoma of the pancreas in experimental animals, we recently established fast-\and slow-growing cultures of acinar cells derived from chemically induced rat pancreatic carcinoma and maintained these cells as corresponding, transplantable subcutaneous tumors in nude mice. Preliminary studies have revealed significant alterations in glucoprotein and lipid metabolism of these tumors. Using both fast-\and slow-growing cancer cells in culture and their corresponding transplantable tumors on nude mice, we have demonstrated: (1)\enhanced cholesterol levels; (2)\enhanced de novo synthesis of cholesterol; (3)\loss of feedback inhibition of de novo synthesis of cholesterol; and (4)\indirect evidence indicating loss of LDL receptors. Based on these results, we put forward the hypothesis that a defect in receptor mediated endocytosis of LDL results in a loss of feedback inhibition of cholesterol synthesis de novo, in the tumor. From the literature and from our results, it is apparent that a relationship between cholesterol and DNA synthesis exists during cell proliferation. The regulation of de novo synthesis of cholesterol by receptor-mediated endocytosis of LDL was not considered when the significance of loss of feedback inhibition of cholesterol synthesis de novo in hepatomas was actively studied. The possibility that the loss of feedback inhibition of cholesterol synthesis, de novo, is one of the adoptive mechanism(s) by the cancer cell to achieve continuous cell proliferation will be examined. The specific aims are to study LDL receptors of fast-\and slow-growing pancreatic acinar cell carcinomas and correlate the down regulation of receptor-mediated endocytosis of LDL with the loss of feedback inhibition of de novo synthesis of cholesterol, and to understand the regulation of LDL receptors of cancer cells by analyzing the synthesis and degradation of cell surface glycoproteins. (A)